Immunomodulator, cell adhesion inhibtor, and agent for treating, and preventing autoimmune diseases

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Claims

1. A method of treating an individual suffering from an autoimmune disease mediated by cell adhesion, comprising:

administering to a patient in need of same a a cell adhesion inhibiting amount of a 4H-1-benzopyran4-one compound represented by the following formula or a salt thereof: ##STR4## wherein R.sup.1 is an unsubstituted or halogen-substituted alkyl, alkenyl or aryl group; R.sup.2 is a hydrogen atom or an alkyl or acyl group; R.sup.3 is a hydrogen or halogen atom or a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R.sup.4 is a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, or a substituted or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, alkynyl, alkenyl, sulfamoyl, alkanesulfinyl, alkanesulfonyl, amidino, phenyl or heterocyclic group or a group of the formula ##STR5## where R.sup.6 is a hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkanesulfonyl, iminomethyl or amidino group and R.sup.7 is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, or R.sup.6 and R.sup.7, when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group; R.sup.5 is a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; Z is an oxygen or sulfur atom or an imino group; and the broken line means a single or double bond.

2. The method of claim 1, wherein R.sup.1 is an unsubstituted or halogen-substituted lower alkyl, lower alkenyl or aryl group; R.sup.2 is a hydrogen atom or an alkyl or acyl group; R.sup.3 is a hydrogen or halogen atom or a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R.sup.4 is a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, or a substituted or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl, lower alkanesulfinyl, lower alkanesulfonyl, amidino, phenyl or heterocyclic group or a group of the formula ##STR6## where R.sup.6 is a hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkanesulfonyl, iminomethyl or amidino group and R.sup.7 is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, or R.sup.6 and R.sup.7, when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered substituted or unsubstituted heterocyclic group; R.sup.5 is a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; Z is an oxygen or sulfur atom or an imino group; and the broken line means a single or double bond.

3. The method of claim 1, wherein R.sup.1 is an unsubstituted or halogen-substituted alkyl group; R.sup.2 is a hydrogen atom; R.sup.3 is a hydrogen atom or a substituted or unsubstituted alkyl group; R.sup.4 is a hydrogen atom, a carboxyl group or a substituted or unsubstituted alkylthio or acylamino group or a carbamoyl group; R.sup.5 is a substituted or unsubstituted phenyl group; Z is an oxygen atom or an imino group and the broken line means a double bond.

4. The method of claim 1, wherein R.sup.1 is an unsubstituted or halogen-substituted lower alkyl group; R.sup.2 is a hydrogen atom; R.sup.3 is a hydrogen atom or a substituted or unsubstituted alkyl group; R.sup.4 is a hydrogen atom, a carboxyl group or a substituted or unsubstituted alkylthio or acylamino group or a carbamoyl group; R.sup.5 is a substituted or unsubstituted phenyl group; Z is an oxygen atom or an imino group and the broken line means a double bond.

5. The method of claim 3, wherein R.sup.3 is a hydrogen atom; R.sup.4 is a substituted or unsubstituted acylamino group; and Z is an oxygen atom.

6. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

7. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

8. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 6-(2,4-difluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one.

9. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

10. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-carbamoyl-2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one

11. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-(N-formyl-N-methyl)amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran -4-one.

12. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

13. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-methylthio-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

14. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 6-(2,4-difluorophenylamino)-3-formylamino-7-methylsulfonylamino-4H-1-benzo pyran-4-one.

15. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 3-carbamoyl-6-(2,4-difluorophenylamino)-7-methylsulfonylamino-4H-1-benzopy ran-4-1-one.

16. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

17. The method of claim 1, wherein said 4H-1-benzopyran-4-one compound is 6-(2-fluorophenylamino)-3-formylamino-7-methylsulfonylamino-4H-1-benzopyra n-4-one.

18. The method of claim 1, wherein said autoimmune disease is chronic rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis/dermatomyositis, Sjogren's syndrome, Bechet's disease, multiple sclerosis, autoimmune diabetes, Hashimoto's disease, psoriasis, primary myxedema, pernicious anemia, myasthenia gravis, ulcerative colitis, chronic active hepatitis, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura.

19. A method of inhibiting cell adhesion, comprising:

administering to a patient in need of same a cell adhesion inhibiting amount of a 4H-1-benzopyran-4-one compound represented by the following formula or a salt thereof: ##STR7## wherein R.sup.1 is an unsubstituted or halogen-substituted alkyl, alkenyl or aryl group; R.sup.2 is a hydrogen atom or an alkyl or acyl group; R.sup.3 is a hydrogen or halogen atom or a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R.sup.4 is a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, or a substituted or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, alkynyl, alkenyl, sulfamoyl, alkanesulfinyl, alkanesulfonyl, amidino, phenyl or heterocyclic group or a group of the formula ##STR8## where R.sup.6 is a hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkanesulfonyl, iminomethyl or amidino group and R.sup.7 is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, or R.sup.6 and R.sup.7, when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered, substituted or unsubstituted heterocyclic group; R.sup.5 is a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; Z is an oxygen or sulfur atom or an imino group; and the broken line means a single or double bond.

20. The method of claim 19, wherein R.sup.1 is an unsubstituted or halogen-substituted lower alkyl, lower alkenyl or aryl group; R.sup.2 is a hydrogen atom or an alkyl or acyl group; R.sup.3 is a hydrogen or halogen atom or a cyano, azido, carboxyl, hydroxyl, formyl or alkoxycarbonyl group or a substituted or unsubstituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R.sup.4 is a hydrogen or halogen atom, a nitro, cyano, carboxyl, acyl, hydroxyl or alkoxycarbonyl group, or a substituted or unsubstituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl, lower alkanesulfinyl, lower alkanesulfonyl, amidino, phenyl or heterocyclic group or a group of the formula ##STR9## where R.sup.6 is a hydrogen atom, a hydroxyl, cyano or alkoxycarbonyl group or a substituted or unsubstituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkanesulfonyl, iminomethyl or amidino group and R.sup.7 is a hydrogen atom or a substituted or unsubstituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, or R.sup.6 and R.sup.7, when taken together with the nitrogen atom to which the two are bonded, form a 3- to 7-membered substituted or unsubstituted heterocyclic group; R.sup.5 is a substituted or unsubstituted phenyl, thienyl, furyl or pyridyl group; Z is an oxygen or sulfur atom or an imino group; and the broken line means a single or double bond.

21. The method of claim 19, wherein R.sup.1 is an unsubstituted or halogen-substituted alkyl group; R.sup.2 is a hydrogen atom; R.sup.3 is a hydrogen atom or a substituted or unsubstituted alkyl group; R.sup.4 is a hydrogen atom, a carboxyl group or a substituted or unsubstituted alkylthio or acylamino group or a carbamoyl group; R.sup.5 is a substituted or unsubstituted phenyl group; Z is an oxygen atom or an imino group and the broken line means a double bond.

22. The method of claim 19, wherein R.sup.1 is an unsubstituted or halogen-substituted lower alkyl group; R.sup.2 is a hydrogen atom; R.sub.3 is a hydrogen atom or a substituted or unsubstituted alkyl group; R.sup.4 is a hydrogen atom, a carboxyl group or a substituted or unsubstituted alkylthio or acylamino group or a carbamoyl group; R.sup.5 is a substituted or unsubstituted phenyl group; Z is an oxygen atom or an imino group and the broken line means a double bond.

23. The method of claim 21, wherein R.sup.3 is a hydrogen atom; R.sup.4 is a substituted or unsubstituted acylamino group; and Z is an oxygen atom.

24. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

25. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

26. The method of claim-19, wherein said 4H-1-benzopyran-4-one compound is 6-(2,4-difluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one.

27. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

28. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-carbamoyl-2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

29. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-(N-formyl-N-methyl)amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran -4-one.

30. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-carboxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

31. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-methylthio-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

32. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 6-(2,4-difluorophenylamino)-3-formylamino-7-methylsulfonylamino-4H-1-benzo pyran-4-one.

33. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 3-carbomoyl-6-(2,4-difluorophenylamino)-7-methylsulfonylamino-4H-1-benzopy ran-4-one.

34. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

35. The method of claim 19, wherein said 4H-1-benzopyran-4-one compound is 6-(2-fluorophenylamino)-3-formylamino-7-methylsulfonylamino-4H-1-benzopyra n-4-one.

Referenced Cited
U.S. Patent Documents
4954518 September 4, 1990 Takaro et al.
5196445 March 23, 1993 Doria et al.
Foreign Patent Documents
2-49778 February 1990 JPX
Other references
  • Tanaka et al, J. Pharmacobio-Dyn., vol. 15, pp. 649-655 (1992).
Patent History
Patent number: 5922755
Type: Grant
Filed: May 6, 1996
Date of Patent: Jul 13, 1999
Assignee: Toyama Chemical Co., Ltd. (Tokyo)
Inventors: Keiichi Tanaka (Toyama), Shinji Makino (Kurobe), Ichiro Oshio (Machida), Tomoya Shimotori (Toyama), Yukihiko Aikawa (Toyama), Takihiro Inaba (Namerikawa), Chosaku Yoshida (Takaoka), Shuntaro Takano (Mitaka), Yoichi Taniguchi (Takaoka)
Primary Examiner: Theodore J. Criares
Law Firm: Oblon, Spivak, McClelland, Maier & Neustadt, P.C.
Application Number: 8/530,177